STAT3 activation in HER2-overexpressing breast cancer promotes epithelial-mesenchymal transition and cancer stem cell traits.
STAT3 activation in HER2-overexpressing breast cancer promotes epithelial-mesenchymal transition and cancer stem cell traits.
复制标题
DOI：
10.3892/ijo.2013.2195
复制
发表时间：
2014-02
影响因子：
5.2
通讯作者：
Vadgama JV
中科院分区：
文献类型：
--
作者：
Chung SS;Giehl N;Wu Y;Vadgama JV
临床上，HER2原癌基因扩增在大约25%-30%的人类乳腺癌中被发现，这与预后不良有关。在大约50-60%的乳腺肿瘤中发现了STAT3的结构性激活，并与肿瘤的发生和耐药有关。在这项研究中，我们发现STAT3在HER2过表达、ER阳性的人乳腺肿瘤中被磷酸化，而且，磷酸化的STAT3促进了干细胞的表型。我们研究了干细胞标记物(OCT-4、SOX-2和CD44)的失调以及HER2过表达的人乳腺癌细胞系中肿瘤球体的形成。我们证明，STAT3抑制剂STATIC治疗取消了HER2阳性乳腺癌中的肿瘤干细胞表型。赫赛汀和他汀类药物联合应用对肿瘤细胞的体外生长有协同作用。此外，当STAT3基因被敲除时，干细胞标记物Oct-4、Sox-2和CD44的表达下调，肿瘤球的形成被取消。HER2诱导的STAT3信号可能为干细胞特性诱导耐药提供了一种潜在的模型。这一机制可能是在治疗HER2过表达的乳腺肿瘤时获得对Herceptin的耐药性的原因。根据我们的发现，靶向pSTAT3可以克服Herceptin诱导的HER2过表达乳腺肿瘤的耐药性。
Clinically, HER2 proto-oncogene amplification is found in about 25–30% of human breast cancers, where it is correlated to a poor prognosis. Constitutive STAT3 activation is found in about 50–60% of the breast tumors and associated with tumorigenesis and drug resistance. In this study, we showed that STAT3 was phosphorylated in HER2-overexpressing, ER-positive human breast tumors and, furthermore, phosphorylated STAT3 promoted the stem-like cell phenotype. We examined the dysregulation of the stem cell markers (Oct-4, Sox-2 and CD44) and the tumorsphere formation in HER2-overexpressing human breast cancer cell lines. We demonstrated that the STAT3 inhibitor, Stattic, treatment abolished the cancer stem cell phenotype in HER2-positive breast cancers. Combined treatment of Herceptin and Stattic showed the synergistic effect on the cancer cell growth in vitro. In addition, when the STAT3 gene was knocked down, the expression of the stem cell markers Oct-4, Sox-2 and CD44 were downregulated and tumorsphere formation was abolished. HER2-elicited STAT3 signaling may provide a potential model for drug resistance induced by stem-like cell characteristics. This mechanism may be responsible for acquiring resistance to Herceptin in the treatment of HER2-overexpressing breast tumors. Based on our findings, targeting pSTAT3 could overcome Herceptin-induced resistance in HER2-overexpressing breast tumors.
登录
查看更多内容
影响因子：
3.5
作者：
Gemmete, J. J.;Mukherji, S. K.
通讯作者：
Mukherji, S. K.
DOI：
10.1186/bcr1680
发表时间：
2007
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Berishaj M;Gao SP;Ahmed S;Leslie K;Al-Ahmadie H;Gerald WL;Bornmann W;Bromberg JF
通讯作者：
Bromberg JF
Twist2通过促进上皮-间质转化和癌症干细胞样细胞自我更新促进乳腺癌进展
影响因子：
8
作者：
Fang, X.;Cai, Y.;Ouyang, G.
通讯作者：
Ouyang, G.
DOI：
10.1016/j.bbrc.2010.05.041
发表时间：
2010-06-18
影响因子：
3.1
作者：
Oliveras-Ferraros, Cristina;Vazquez-Martin, Alejandro;Menendez, Javier A.
通讯作者：
Menendez, Javier A.
影响因子：
5.3
作者：
Hsu, Han-Shui;Lin, Jiun-Han;Hung, Shih-Chieh
通讯作者：
Hung, Shih-Chieh